(TRAIL)-Mediated Apoptosis by Helicobacter Pylori in Immun

+ MODEL Journal of Microbiology, Immunology and Infection (2016) xx,1e6

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REVIEW ARTICLE Modulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by Helicobacter pylori in immune pathogenesis of gastric mucosal damage Hwei-Fang Tsai a,b, Ping-Ning Hsu c,d,* a Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, Taipei, Taiwan b Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan c Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan d Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

Received 1 March 2015; received in revised form 20 December 2015; accepted 17 January 2016 Available online ---

KEYWORDS Abstract Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, apoptosis; gastric carcinoma, and gastric mucosa-associated lymphoid tissue lymphomas. Apoptosis chemokine; induced by microbial infections is implicated in the pathogenesis of H. pylori infection. FLIP; Enhanced gastric epithelial cell apoptosis during H. pylori infection was suggested to play Helicobacter pylori; an important role in the pathogenesis of chronic gastritis and gastric pathology. In addition TRAIL to directly triggering apoptosis, H. pylori induces sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in gastric epithelial cells. Human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death-receptor signaling. The induction of TRAIL sensitivity by H. pylori is dependent upon the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex through downregulation of cellular FLICE-inhibitory protein. Moreover, H. pylori infection induces infiltration of T lymphocytes and triggers inflammation to augment apoptosis. In H. pylori infection, significant increases in CCR6þ CD3þ T cell infiltration in the gastric mucosa was observed, and the CCR6 ligand, CCL20 chemokine, was selectively expressed in inflamed gastric tissues. These mechanisms initiate chemokine-mediated T lymphocyte trafficking into inflamed epithelium and induce mucosal injury during Helicobacter infection. This article will review recent findings on the interactions of H. pylori with host-epithelial signaling pathways and events involved in the initiation of gastric pathology, including gastric inflammation and mucosal damage.

* Corresponding author. Graduate Institute of Immunology, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Section 1, Taipei 100, Taiwan. E-mail address: [email protected] (P.-N. Hsu). http://dx.doi.org/10.1016/j.jmii.2016.01.002 1684-1182/Copyright ª 2016, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Tsai H-F, Hsu P-N, Modulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- mediated apoptosis by Helicobacter pylori in immune pathogenesis of gastric mucosal damage, Journal of Microbiology, Immunology and Infection (2016), http://dx.doi.org/10.1016/j.jmii.2016.01.002 + MODEL 2 H.-F. Tsai, P.-N. Hsu

Copyright ª 2016, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/).

Helicobacter pylori infection and apoptosis in homology with FasL that is capable of inducing apoptosis in 22,23 gastric epithelial cells a variety of transformed cell lines in vitro, but usually not in normal primary cells. T cells can kill target cells via TRAIL/TRAIL-receptor interaction,24,25 indicating that Helicobacter pylori is a common human pathogen that in- TRAIL might serve as a cytotoxic effector molecule in fects over half of the world population and is associated activated T cells in vivo. These findings suggested that with duodenal and peptic ulcer diseases. The clinical con- TRAIL/TRAIL-receptor interaction is involved in the inter- sequences range from asymptomatic gastritis to peptic ul- action between infiltrating T cells and gastric epithelium ceration and gastric malignancy.1,2 The outcome of the during H. pylori gastritis. Recent studies demonstrated that infection is determined by interactions among H. pylori human gastric epithelial cells sensitized to H. pylori confer virulence factors, host gastric mucosal factors, and the susceptibility to TRAIL-mediated apoptosis, suggesting a environment. However, the mechanisms by which host role for immune-mediated apoptosis in gastric epithelial factors cause disease remain unclear. Apoptosis induced by cells by infiltrating T cells during Helicobacter infec- microbial infections is implicated in the pathogenesis of H. tion.6,14,26 The induction of TRAIL sensitivity by H. pylori is pylori infection, and enhanced gastric epithelial cell dependent upon bacterial cell contact, irrespective of apoptosis during H. pylori infection was suggested to play expression of H. pylori virulent factors.6 an important role in the pathogenesis of chronic gastritis e TRAIL-induced apoptosis occurs through a caspase and gastric pathology.3 7 Direct cytotoxicity, as well as signaling cascade, and resistance to TRAIL is controlled by inflammatory responses, occurs in gastric mucosa e intracellular regulators of apoptosis. Crosslinking of the cells.5,8 10 H. pylori vacuolating (VacA) toxin induces TRAIL receptors leads to the formation of a death-inducing gastric epithelial cell apoptosis, but cytotoxin-associated signaling complex (DISC)27 assembled by the death-adaptor gene A (CagA) attenuates apoptosis in gastric epithelial protein Fas-associated death-domain protein (FADD) and cells. Bacterial virulent factors may contribute directly to e caspase-8 and -10.28 30 Activated caspase-8 is generated apoptosis in epithelial cells, whereas the induction of after DISC formation, and initiates apoptosis-inducing cas- sensitivity to death-receptor mediated apoptosis by H. py- pase signaling cascade. Previous studies demonstrated that lori is independent of H. pylori virulent factors VacA and TRAIL-induced apoptosis could be enhanced by Heli- CagA,6 suggesting that immune factors, in addition to cobacter and hepatitis C virus core proteins6,31; however, bacterial factors, are also important in determining the the mechanisms leading to microbe-induced TRAIL sensi- degree of gastric mucosa damage during H. pylori infection. tivity remain unclear. H. pylori-induced sensitivity to It was demonstrated that T helper type 1 (Th1) cells e TRAIL-mediated apoptosis in gastric epithelial cells is selectively increased during H. pylori infection.11 14 Th1 cy- dependent upon activation of the caspase-8 downstream tokines, such as interferon gamma (IFN-g) and tumor necrosis pathway for conveyance of death signals to mitochondria, factor alpha (TNF-a), can increase the release of proin- resulting in activation of mitochondrial pathways and flammatory cytokines, augmenting apoptosis induced by H. removing resistance to apoptosis. H. pylori also induces pylori.10 H. pylori infection could also induce gastric mucosa sensitivity to TRAIL-mediated apoptosis by regulation of damage by increasing expression of Fas in gastric epithelial FLICE-inhibitory protein (FLIP) and assembly of DISC, which cells, leading to gastric epithelial cell apoptosis through Fas/ initiates caspase activation26 and promotes apoptosis, Fas ligand (FasL) interaction with infiltrating T cells.9,15 These thereby providing insight into the pathogenesis of gastric findings suggest a role for immune-mediated apoptosis of damage during Helicobacter infection (Figure 1). Modula- gastric epithelial cells during H. pylori infection. Additionally, tion of host-cell apoptosis by bacterial interaction adds a H. pylori directly triggers cell death by cytotoxins after new dimension to immune pathogenesis associated with interacting with gastric epithelial cells.16,17 Furthermore, H. Helicobacter infection. pylori translocates CagA into gastric epithelial cells by Type IV secretion, inducing intracellular protein phosphorylation and dysregulating signal transduction pathways within host cells.18e21 In addition to directly triggering apoptosis, it is Chemokine-mediated lymphocyte trafficking possible that H. pylori induces sensitivity to apoptosis in of T lymphocytes in gastric inflammation gastric epithelial cells via modulation of apoptosis signaling. during H. pylori infection

H. pylori modulate tumor necrosis factor- During H. pylori infection, the degree of apoptosis induced in the stomach is affected by the inflammatory response. H. related apoptosis-inducing ligand (TRAIL)- pylori infection induces a T cell response, as well as a mediated apoptosis in gastric epithelial cells number of inflammatory mediators, including cytokines and chemokines.7,11,14,32 These infiltrating T cells can then TNF-related apoptosis-inducing ligand (TRAIL; also called target and destroy gastric cells via TRAIL/TRAIL-receptor Apo2L) is a novel TNF superfamily member with strong interaction. In addition to its role in inducing apoptosis by

Figure 1. Helicobacter pylori modulates TRAIL-mediated apoptosis in gastric epithelial cells. H. pylori enhances assembly of TRAIL death inducing signaling complex (DISC) through downregulation of FLIP after TRAIL engagement, to activate caspase 8 cleavage, and to convey the death signal to mitochondria via cleavage of Bid, leading to activation of mitochondrial pathway and breaking the apoptosis resistance. DED Z death effector domain; DD Z death domain; DR4 Z death receptor 4; DR5 Z death receptor 5; FADD Z Fas-associated death-domain protein; FLIP Z FLICE-inhibitory protein; TRAIL Z tumor necrosis factor-related apoptosis-inducing ligand. binding to death receptors, TRAIL can directly stimulate pylorieassociated diseases. These results indicate that im- T cells by binding to TRAIL receptors and transducing a mune reaction and inflammation mediators associated with H. reverse signal to T cells in conjunction with T cell receptor pylori plays an important role in the pathogenesis of H. pylori- engagement, resulting in T cell proliferation and augment- associated diseases. Among T cells responding to H. pylori ing IFN-g secretion.33e35 Therefore, these results support a infection, gastric-infiltrating T cells are mostly functional role of TRAIL in H. pylori-induced apoptosis. CD45ROþCD69þCD4þT cells, indicating an accumulation of Moreover, the degree of apoptosis during H. pylori infection activated memory CD4þ T cells during Helicobacter infec- may also be linked to the associated inflammatory response. tion.14 Recent reports indicated that Th1 and Th17 responses Therefore, in addition to H. pylori virulence, mucosal were induced during H. pylori infection,11,14,32 and that levels damage may also be affected by the inflammatory response of IFN-g and TNF-a increased in the gastric mucosa during H. induced by H. pylori within the gastric epithelium. pylori infection, augmenting H. pylori-induced Inflammation of the gastric mucosa develops in response to apoptosis.5,6,10 These results suggest a role for immune- host immune reaction against pathogens. The stimulation of mediated apoptosis in gastric epithelial cells by infiltrating epithelial cells by H. pylori contributes to neutrophil and T cells during Helicobacter infection. However, the induction lymphocyte recruitment. As described, the features of H. of immune responses and the immunopathogenic mecha- pylori-induced inflammatory immune response are orches- nism(s) of mucosal inflammation during H. pylori infections trated by sequential elaboration of proinflammatory cyto- remain unclear, with chemokines thought to play an impor- kines, including interleukin (IL)-10, IFN-g,TNF-a, and IL-1b. tant role in this process.36,37 Chemokines are involved in acute Accordingly, factors involved in regulating cytokine responses and chronic inflammatory processes by attracting neutro- may confer susceptibility to or protection against H. phils, monocytes, and T cells to the site of inflammation via

Figure 2. Immune pathogenesis of gastric mucosa damage in Helicobacter pylori infection. In the absence of H. pylori infection, there are very few infiltrating T cells recruited into the gastric mucosa. When T cells interact with human gastric epithelial cells in the presence of H. pylori infection, there are increased CCR6þ activated T cells infiltrated into gastric mucosa via CCL20 induced by H. pylori. The infiltrated activated T cells are recruited into gastric mucosa via CCR6, and then induce apoptosis to gastric epithelial cells via TRAIL/TRAIL receptor interaction. CagA Z cytotoxin-associated gene A; DR4 Z death receptor 4; DR5 Z death receptor 5; TRAIL Z tumor necrosis factor-related apoptosis-inducing ligand. their corresponding chemokine receptors.38,39 Recent reports activation of caspase-8 and its downstream pathway via showed that there are specific chemokines that mediate the enhanced assembly of the TRAIL DISC through down- homing of lymphocytes in the intestines,37,40 suggesting that regulation of cellular FLIP. The degree of mucosal damage some chemokines may be involved in lymphocyte trafficking is also affected by the inflammatory response induced by H. in the gut. A set of proinflammatory chemokines are also pylori within the gastric epithelium. These results suggest a involved in H. pylori gastritis: Gro-a, IL-8, RANTES, IFN-g- role for immune-mediated apoptosis and mucosa damage inducible protein-10 (IP-10; CXCL10), a monokine induced by by infiltrating T cells during Helicobacter infection. In IFN-g (MIG, CXCL11), and CCL20 (MIP-3a/LARC/ conclusion, H. pylori enhances susceptibility of gastric exodus).14,41,42 It was demonstrated that the gastrointestinal epithelial cells to TRAIL-mediated apoptosis via modulation epithelium senses invading microorganisms and produces cy- of death-receptor signaling. Modulation of host-cell tokines/chemokines that attract lymphocytes and dendritic apoptosis by bacterial interaction adds a new dimension cells to the site of inflammation.43 Recently, it was reported to the immune pathogenesis associated with chronic Heli- that CCR6 mediates dendritic cell localization, lymphocyte cobacter infection. homeostasis, and immune responses in mucosal tissue.44 CCR6, a specific b-chemokine receptor for CCL20, is selec- Conflicts of interest tively expressed on dendritic cells and some memory Tcells,43,45,46 and may play a role in chemokine-mediated The authors declare no conflicts of interest. lymphocyte trafficking during gastric inflammation. Addi- tionally, CCL20, the ligand of CCR6, is abundantly expressed in mouse and human inflammatory enteric mucosa,47 and CCL20 Acknowledgments production was upregulated in response to H. pylori in gastric epithelial cells when there was stimulation by the proin- 14,48e50 This work was supported by grants from the National Sci- flammatory cytokines IL-1b and TNF-a. These results ence Council, Taiwan (NSC98-3112-B-002-047, NSC101- implicated the interaction between CCL20 and CCR6 in 2320-B-038-019-, and NSC 101-2321-B-002-008-). recruiting CD45ROþ memory T cells to sites of inflammation in the gastric mucosa during Helicobacter infection (Figure 2).14 References Conclusion 1. Parsonnet J, Friedman GD, Vandersteen DG, Chang Y, Vogelman JH, Orentreich N, et al. Helicobacter pylori infection Human gastric epithelial cells sensitized to H. pylori confer and risk of gastric carcinoma. N Engl J Med 1994;325:1127e31. susceptibility to TRAIL-mediated apoptosis, and the induc- 2. Peek RMJ, Blaser MJ. Helicobacter pylori and gastrointestinal tion of TRAIL sensitivity by H. pylori is dependent upon the tract adenocarcinomas. Nat Rev Cancer 2002;2:28e37.

3. Jones N, Shannon PT, Cutz E, Yeger H, Sherman PM. Increase in 20. Odenbreit S, Puls J, Sedlmaier B, Gerland E, Fischer W, Haas R. proliferation and apoptosis of gastric epithelial cells early in Translocation of Helicobacter pylori CagA into gastric epithe- the natural history of Helicobacter pylori infection. Am J lial cells by type IV secretion. Science 2000;287:1497e500. Pathol 1997;151:1685e703. 21. Stein M, Rappuoli R, Covacci A. Tyrosine phosphorylation of the 4. Moss S, Calam J, Agarwal B, Wang S, Holt PR. Induction of Helicobacter pylori CagA antigen after cag-driven host cell gastric epithelial apoptosis by Helicobacter pylori. Gut 1996; translocation. Proc Natl Acad Sci USA 2000;97:1263e8. 38:498e501. 22. Griffith TS, Lynch DH. TRAIL: a molecule with multiple re- 5. Rudi J, Kuck D, Strand S, von Herbay A, Mariani SM, ceptors and control mechanisms. Curr Opin Immunol 1998; Krammer PH, et al. Involvement of the CD95 (APO-1/Fas) re- 10:559e63. ceptor and ligand system in Helicobacter pylori-induced 23. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, gastric epithelial apoptosis. J Clin Investig 1998;102: et al. Identification and characterization of a new member of 1506e14. the TNF family that induces apoptosis. Immunity 1995;3: 6. Wu YY, Tsai HF, Lin WC, Chou AH, Chen HT, Yang JC, et al. 673e82. Helicobacter pylori enhances tumor necrosis factor-related 24. Kayagaki N, Yamaguchi N, Nakayama M, Eto H, Okumura K, apoptosis-inducing ligand-mediated apoptosis in human Yagita H. Type I interferons (IFNs) regulate tumor necrosis gastric epithelial cells. World J Gastroenterol 2004;10: factor-related apoptosis-inducing ligand (TRAIL) expression on 2334e9. human T cells: a novel mechanism for the antitumor effects of 7. Tsai HF, Hsu PN. Interplay between Helicobacter pylori and type I IFNs. J Exp Med 1999;189:1451e60. immune cells in immune pathogenesis of gastric inflammation 25. Thomas WD, Hersey P. TNF-related apoptosis-inducing ligand and mucosal pathology. Cell Mol Immunol 2010;7:255e9. (TRAIL) induces apoptosis in Fas ligand-resistant melanoma 8. Fan XJ, Crowe SE, Behar S, Gunasena H, Ye G, Haeberle H, cells and mediates CD4 T cell killing of target cells. J Immunol et al. The effect of class II MHC expression on adherence of 1998;161:2195e200. Helicobacter pylori and induction of apoptosis in gastric 26. Lin WC, Tsai HF, Liao HJ, Tang CH, Wu YY, Hsu PI, et al. Heli- epithelial cells: a mechanism for Th1 cell-mediated damage. J cobacter pylori sensitizes TNF-related apoptosis-inducing Exp Med 1998;187:1659e69. ligand (TRAIL)-mediated apoptosis in human gastric epithelial 9. Jones N, Day A, Jennings HA, Sherman PM. Helicobacter pylori cells through regulation of FLIP. Cell Death Dis 2014;6:e1109. induces gastric epithelial cell apoptosis in association with 27. Walczak H, Sprick MR. Biochemistry and function of the DISC. increased Fas receptor expression. Infect Immun 1999;67: Trends Biochem Sci 2001;26:452e3. 4237e42. 28. Bodmer JL, Holler N, Reynard S, Vinciguerra P, Schneider P, 10. Wagner S, Beil W, Westermann J, Logan RPH, Bock CT, Juo P, et al. TRAIL receptor-2 signals apoptosis through FADD Trautwein C, et al. Regulation of epithelial cell growth by and caspase-8. Nat Cell Biol 2000;2:241e3. Helicobacter pylori: evidence for a major role of apoptosis. 29. Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Gastroenterology 1997;113:1836e47. Ashkenazi A. Apo2L/TRAIL-dependent recruitment of endoge- 11. Bamford KB, Fan XJ, Crowe SE, Leary JF, Gourley WK, nous FADD and caspase-8 to death receptors 4 and 5. Immunity Luthra GK, et al. Lymphocytes in the human gastric mucosa 2000;12:611e20. during Helicobacter pylori have a T helper cell 1 phenotype. 30. Sprick MR, Weigand MA, Rieser E, Rauch CT, Juo P, Blenis J, Gastroenterology 1998;114:482e92. et al. FADD/MORT1 and caspase-8 are recruited to TRAIL re- 12. Elios MM, Manghetti M, De Carli M, Costa F, Baldari CT, ceptors 1 and 2 and are essential for apoptosis mediated by Burroni D, et al. T helper 1 effector cells specific for Heli- TRAIL receptor 2. Immunity 2000;12:599e609. cobacter pylori in gastric antrum of patients with peptic ulcer 31. Chou AH, Tsai HF, Wu YY, Hu CY, Hwang LH, Hsu PI, et al. disease. J Immunol 1997;158:962e7. Hepatitis C virus core protein modulates TRAIL-mediated 13. Karttunen R, Karttunen T, Ekre HPT, MacDonald TT. Interferon apoptosis by enhancing Bid cleavage and activation of mito- gamma and interleukin 4 secreting cells in the gastric antrum chondria apoptosis signaling pathway. J Immunol 2005;174: in Helicobacter pylori positive and negative gastritis. Gut 2160e6. 1995;36:341e5. 32. Munari F, Fassan M, Capitani N, Codolo G, Vila-Caballer M, 14. Wu YY, Tsai HF, Lin WC, Hsu PI, Shun CT, Wu MS, et al. Upre- Pizzi M, et al. Cytokine BAFF released by Helicobacter pylori- gulation of CCL20 and recruitment of CCR6 gastric infiltrating infected macrophages triggers the Th17 response in human lymphocytes in Helicobacter pylori gastritis. Infect Immun chronic gastritis. J Immunol 2014;193:5584e94. 2007;75:4357e63. 33. Chou AH, Tsai HF, Lin LL, Hsieh SL, Hsu PI, Hsu PN. Enhanced 15. Wang J, Fan X, Lindholm C, Bennett M, O’Connoll J, proliferation and increased IFN-gamma production in T cells by Shanahan F, et al. Helicobacter pylori modulates lymphoepi- signal transduced through TNF-related apoptosis inducing thelial cell interactions leading to epithelial cell damage ligand. J Immunol 2001;167:1347e52. through Fas/Fas ligand interactions. Infect Immun 2000;68: 34. Tsai HF, Lai JJ, Chou AH, Wang TF, Wu CS, Hsu PN. Induction of 4303e11. costimulation of human CD4 T cells by tumor necrosis factor- 16. Kuck D, Kolmerer B, Iking-Konert C, Krammer PH, Stremmel W, related apoptosis-inducing ligand: possible role in T cell acti- Rudi J. Vacuolating cytotoxin of Helicobacter pylori induces vation in systemic lupus erythematosus. Arthritis Rheum 2004; apoptosis in the human gastric epithelial cell line AGS. Infect 50:629e39. Immun 2001;69:5080e7. 35. Huang SC, Tsai HF, Tzeng HT, Liao HJ, Hsu PN. Lipid raft as- 17. Le’Negrate G, Ricci V, Hofman V, Mograbi B, Hofman P, Rossi B. sembly and Lck recruitment in TRAIL costimulation mediates Epithelial intestinal cell apoptosis induced by Helicobacter NF-kB activation and T cell proliferation. J Immunol 2011;186: pylori depends on expression of the cag pathogenicity Island 931e9. phenotype. Infect Immun 2001;69:5001e9. 36. Campbell J, Butcher EC. Chemokines in tissue-specific and 18. Asahi BM, Azuma T, Ito S, Ito Y, Suto H, Nagai Y, et al. Heli- microenvironment-specific lymphocyte homing. Curr Opin cobacter pylori CagA protein can be tyrosine phosphorylated in Immunol 2000;12:336e41. gastric epithelial cells. J Exp Med 2000;191:593e602. 37. Dwinell MB, Lugering N, Eckmann L, Kagnoff MF. Regulated 19. Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, production of interferon-inducible T-cell chemoattractants by et al. SHP-2 tyrosine phosphatase as an intracellular target of human intestinal epithelial cells. Gastroenterology 2001;120: Helicobacter pylori CagA. Science 2002;295:683e6. 49e59.

38. Baggiolini M. Chemokines and leukocyte traffic. Nature 1998; interacts with macrophage inflammatory protein 3a and is 392:565e8. highly expressed in human dendritic cells. J Exp Med 1997;186: 39. Luster AD. Chemokines: chemotactic cytokines that mediate 837e42. inflammation. N Engl J Med 1998;338:436e45. 46. Liao F, Rabin RL, Smith CS, Sharma G, Nutman TB, Farber JM. 40. Papadakis KA, Prehn J, Nelson V, Cheng L, Binder SW, CC-chemokine receptor 6 is expressed on diverse memory Ponath PD, et al. The role of thymus-expressed chemokine and subsets of T cells and determines responsiveness to macro- its receptor CCR9 on lymphocytes in the regional specialization phage inflammatory protein 3 alpha. J Immunol 1999;162: of the mucosal immune system. J Immunol 2000;165:5069e76. 186e94. 41. Wen S, Felley CP, Bouzourene H, Reimers M, Michetti P, Pan- 47. Tanaka Y, Imai T, Baba M, Ishikawa I, Uehira M, Nomiyama H, Hammarstrom Q. Inflammatory gene profiles in gastric mucosa et al. Selective expression of liver and activation-regulated during Helicobacter pylori infection in humans1. J Immunol chemokine (LARC) in intestinal epithelium in mice and 2004;172:2595e606. humans. Eur J Immunol 1999;29:633e42. 42. Yamaoka Y, Kita M, Kodama T, Sawai N, Tanahashi T, 48. Nishi T, Okazaki K, Kawasaki K, Fukui T, Tamaki H, Matsuura M, Kashima K, et al. Chemokines in the gastric mucosa in Heli- et al. Involvement of myeloid dendritic cells in the develop- cobacter pylori infection. Gut 1998;42:609e17. ment of gastric secondary lymphoid follicles in Helicobacter 43. Baba M, Imai T, Nishimura M, Kakizaki M, Takagi S, Hieshima K, pylori-infected neonatally thymectomized BALB/c mice. Infect et al. Identification of CCR6, the specific receptor for a novel Immun 2003;71:2153e62. lymphocyte-directed CC chemokine LARC. J Biol Chem 1997; 49. Tomimori K, Uema E, Teruya H, Ishikawa C, Okudaira T, 272:14893e901. Senba M, et al. Helicobacter pylori induces CCL20 expression. 44. Cook DN, Prosser DM, Forster R, Zhang J, Kuklin NA, Infect Immun 2007;75:5223e32. Abbondanzo SJ, et al. CCR6 mediates dendritic cell localiza- 50. Yoshida A, Isomoto H, Hisatsune J, Nakayama M, Nakashima Y, tion, lymphocyte homeostasis, and immune responses in Matsushima K, et al. Enhanced expression of CCL20 in human mucosal tissue. Immunity 2000;12:495e503. Helicobacter pylori-associated gastritis. Clin Immunol 2009; 45. Greaves DR, Wang W, Dairaghi DJ, Dieu MC, Saint-Vis BD, 130:290e7. Franz-Bacon K, et al. CCR6, a CC chemokine receptor that